Estrogen plays a crucial role in coordinating the neuroendocrine events that control sexual development, sexual behavior and reproduction. Additionally, estrogen modulates numerous additional facets of brain function. In humans, the primary biologically active form of estrogen is 172-estradiol (E2). E2 has been implicated in several non-reproductive brain functions such as protection against brain injury, involvement in learning and memory as well as promoting the formation of synapses. Additionally, a growing body of literature has shown that E2 treatment may alleviate neuronal dysfunctions from Alzheimer<s disease through multifaceted molecular and cellular mechanisms. During aging, cognitive and neurodegenerative conditions increase. In particular postmenopausal women are increasingly vulnerable as their E2 levels precipitously decline. As women spend a larger proportion of their lives in a hypoestrogenic state, it is critical to understand the underlying mechanisms of estrogen action in the brain. Data from the Women<s Health Initiative suggest that current hormonal therapies, however, do not prevent cognitive decline. One potential reason for this observation is that the timing of hormone replacement is critical and thus changes in estrogen receptor expression in the brain may over-ride any potential hormonal intervention. Estrogen receptor-alpha splice variants have been shown to be associated with neurological disorders in the aging human brain, however little is known about estrogen receptor-beta expression in the aging human brain. In rodents, however, ER2 mRNA expression is modified by age. ER2 expression decreases in a brain region specific manner, although the cause of this decline is not known. ER2 expression in the cortex and other brain regions could be regulated by a variety of mechanisms. One potential mechanism of ER2 gene regulation is through epigenetic modification of C-G rich regions of the ER1 promoter by methylation or acetylation of histones associated with the gene. Gene silencing occurs when methyl-binding proteins become associated with the methylated region of DNA, which prevents transcription machinery from binding. Examples of epigenetic regulation of ER2 are seen in breast and prostate cancer where ER2 expression has been correlated with changes in methylation. Although regulation of ER2 expression has been heavily studied in cancer models, very little is known about epigenetic regulation of ER2 in the brain during aging. Understanding how methylation alters gene expression in the brain may lead to the development of interventional strategies to influence gene expression related to human neurological disease. This proposal tests the hypothesis that estrogen receptor-beta gene expression is regulated by epigenetic mechanisms in the aging female brain. PUBLIC HEALTH RELEVANCE: These studies will begin to determine the novel mechanisms of changes in gene expression caused by age on a critical gene in the female brain. These insights could lead to development of therapeutics that result in improved cognition in the postmenopausal woman by potentially preventing changes in ER2 gene expression. Furthermore, we will develop a new methodology that will be critical for examining epigenetic changes in gene expression in a temporal and spatial manner in neural tissue with heterogeneous cell populations.